Notwithstanding excellent studies on the nature of antigenic determinants in globular proteins, there is still relatively little systematic information on which structures will and which will not constitute such a determinant in a natural globular protein. Direct approaches to this problem have been difficult because of the relatively small number of proteins of known primary and tertiary structure, and even more importantly because of the lack of sufficient appropriate variants. Cytochrome c presents an excellent model for such studies. The spatial structural of the protein is known and is constant for different species. Moreover, among the 60 cytochromes c whose amino acid sequences have been determined to date, a large range of variant proteins can be selected, with as few or as many protein surface or protein internal changes as required to examine various molecular and biological aspects of the immune response. These include the effectiveness of different globular protein structures, natural and chemically varied, to induce the antibody response, and also to induce and break immunological tolerance. The possible correlations between the number of the same and of different antigenic determinant sites per molecular particle, the size of such particles, the molecular geometry of antigenic sites and the magnitude and nature of the response, will be examined. Whether the effects of such parameters are related to the type of immunocompetent cell involved and whether these parameters influence tolerance phenomena, will be studied. This work will require the isolation of site-specific antibody populations which may make it possible to relate the number of single clonal products to the chemical nature of individual determinants. The potential of such studies is in providing a significant part of the understanding of the immune response which will be necessary for its eventual control at the molecular level.